The present invention relates to improved methods for preparing aryl hydrazines, aryl hydrazones, O-aryl hydroxylamines, N-aryl hydroxylamines, O-aryl oximes and the like which are useful intermediates and end products in pharmaceutical and agricultural applications. Certain products of the present invention are utilized in a novel entry into the classical Fischer indole synthesis.
Despite the recent successes with palladium-catalyzed cross-coupling reactions of Arxe2x80x94X with amines, comparable couplings of aryl halides with hydrazines and the like have not been reported. Existing methods for the conversion of Arxe2x80x94X to the corresponding aryl hydrazines often require harsh or restrictive reaction conditions and/or the presence of activating groups on the aromatic ring.
Thus there remains a need for an effective method of preparing a wide range of aryl hydrazines and the like under mild conditions and in high yields. There is a further need for an efficient catalytic system with high efficiencies and turnover numbers for the synthesis of these compounds.
The present invention provides general and attractive routes to a wide range of aryl hydrazines, aryl hydrazones, O-aryl hydroxylamines, N-aryl hydroxylamines, O-aryl oximes and the like. The methods provide several improvements over methods known heretofore, namely, the efficient synthesis of these compounds under mild conditions and in high yields. In particular, the method of the invention may be used in coupling reactions between aryl halides or sulfonates and ketone or aldehyde hydrazones; the products of these coupling reactions provide indoles via the Fischer indole synthesis. In other aspects of the invention, the invention provides a means of synthesizing combinatorial libraries of indoles, carbazoles and the like.
Overview
In one aspect of the invention, an aryl hydrazine is prepared by reacting hydrazine, or a substituted hydrazine, or a hydrazide salt, with an activated aromatic compound in the presence of a base and a metal catalyst that includes a Group VIII metal atom such as iron, cobalt, nickel, ruthenium, rhodium, palladium, iridium and platinum; Group 10 metalsxe2x80x94platinum, palladium and nickelxe2x80x94are the most preferred metals. The activated aromatic compound comprises an activated substituent, X, which generally is selected from the group comprising halides and sulfonate esters. When the reaction takes place using an hydrazide salt, an additional base may not be required.
In preferred embodiments, the subject synthetic reaction can be characterized by the general reaction scheme shown below: 
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents NR2, OR, Nxe2x95x90CR2, N(R)S(O)2R, or N(R)C(O)NR2;
R represents independently for each occurrence, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8,
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In additional preferred embodiments, the subject synthetic reaction can be characterized by the general reaction scheme shown below: 
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents O, S, or Se;
R independently for each occurrence is absent or represents, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, an alkylidene moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8,
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In further preferred embodiments, the subject reaction may be an intramolecular reaction. In this instance, it will be realized that, with reference to Scheme 1, YNHR is covalently attached to Ar via T which represents a tether between Ar and Y. The intramolecular reaction results in a product containing at least one more ring than the substrate and said reaction can be represented as follows in Scheme 3: 
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X and Txe2x80x94Yxe2x80x94NHR);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents NR, O, sp2-hybridized N in a xcfx80-bond to T, NS(O)2R, or NC(O)NR2;
T represents a covalent tether connecting Y and Ar, said tether comprising between 0 and 4 backbone atoms; the backbone of said tether may comprise a r-bond, provided that the configuration of said xcfx80-bond is such that the described intramolecular reaction is geometrically feasible, or that said xcfx80-bond can adopt a configuration under the reaction conditions that renders the intramolecular reaction geometrically feasible; said tether additionally may itself be either unsubstituted or bear any number of substituents of any type permitted by stability and the rules of valence;
R independently for each occurrence represents, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8;
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In additional preferred embodiments, the subject reaction may be another form of intramolecular reaction. In this instance, it will be realized that, with reference to Scheme 2, N(R)YH is covalently attached to Ar via T which represents a tether between Ar and N. The intramolecular reaction results in a product containing at least one more ring than the substrate and said reaction can be represented as follows in Scheme 4: 
wherein
Ar represents an aromatic group (which may be furthered substituted beyond X and Txe2x80x94NRxe2x80x94YH);
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction;
Y represents O, S, or Se;
T represents a covalent tether connecting NR and Ar, said tether comprising between 0 and 4 backbone atoms; the backbone of said tether may comprise a xcfx80-bond, provided that the configuration of said xcfx80-bond is such that the described intramolecular reaction is geometrically feasible, or that said xcfx80-bond can adopt a configuration under the reaction conditions that renders the intramolecular reaction geometrically feasible; said tether additionally may itself be either unsubstituted or bear any number of substituents of any type permitted by stability and the rules of valence;
R represents independently for each occurrence, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8;
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
m is an integer in the range 0 to 8 inclusive.
In another embodiment, the subject synthetic reaction can be characterized by the general reaction scheme shown below in Scheme 5: 
wherein
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed vinylation reaction;
Y represents NR2, OR, Nxe2x95x90CR2, N(R)S(O)2R, or N(R)C(O)NR2;
R represents independently for each occurrence, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8;
Rxe2x80x2 represents independently for each occurrence, as valence and stability permit, H, halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl group (e.g. ester, carboxylate, or formate), thiocarbonyl (e.g. thiolester, thiolcarboxylate, or thiolformate), ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, xe2x80x94(CH2)mxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94O-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94SH, xe2x80x94(CH2)mxe2x80x94S-lower alkyl, xe2x80x94(CH2)mxe2x80x94S-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94R8, or protecting groups of the above, or a solid or polymeric support;
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
n and m are integers independently for each occurrence selected from the range of 0 to 8 inclusive.
In yet another embodiment, the subject synthetic reaction can be characterized by the general reaction scheme shown below in Scheme 6: 
wherein
X represents an activated group (such as a halide or a sulfonate), which can be replaced by a nucleophilic nitrogen in a transition metal-catalyzed vinylation reaction;
Y represents O, S, or Se;
R independently for each occurrence is absent or represents, as valence and stability permit, H, a substituted or unsubstituted alkyl or alkenyl moiety, an alkylidene moiety, a formyl, acyl, or sulfonyl moiety, or xe2x80x94(CH2)mxe2x80x94R8;
Rxe2x80x2 represents independently for each occurrence, as valence and stability permit, H, halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl group (e.g. ester, carboxylate, or formate), thiocarbonyl (e.g. thiolester, thiolcarboxylate, or thiolformate), ketone, aldehyde, amino, acylamino, amido, amidino, cyano, nitro, azido, sulfonyl, sulfoxido, sulfate, sulfonate, sulfamoyl, sulfonamido, phosphoryl, phosphonate, phosphinate, xe2x80x94(CH2)mxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94O-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94SH, xe2x80x94(CH2)mxe2x80x94S-lower alkyl, xe2x80x94(CH2)mxe2x80x94S-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94R8, or protecting groups of the above, or a solid or polymeric support;
R8 represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; and
n and m are integers independently for each occurrence selected from the range of 0 to 8 inclusive.
Artisans of ordinary skill will recognize the potential for intramolecular variants of the vinylation reactions presented in Schemes 5 and 6. Specifically, a comparison of the embodiment of the subject method depicted in Scheme 1 with that in Scheme 3, and a similar comparison of the embodiments depicted in Schemes 2 and 4, will serve to teach the embodiments that comprise an intramolecular vinylation reaction.
While not being bound by any particular mode of operation, it is hypothesized that the mechanism of the preferred Pd-catalyzed arylation of hydrazines and the like may proceed via a pathway similar to that depicted in Scheme 7. Scheme 7 presents a proposed reaction pathway for the synthesis of an aryl hydrazine via an intermolecular reaction. Any ligands that may be present on the palladium atom during this process have been omitted for clarity. With reference to Scheme 7, oxidative addition of the Pd(0) complex to the Cxe2x80x94X bond of the activated aryl moiety (ArX) affords the Pd(II) organometallic intermediate A. The hydrazine could then displace Xxe2x88x92 from A and thereby generate cation B. Cation B would then suffer deprotonation to afford charge neutral intermediate C, which would subsequently undergo reductive elimination to yield the product aryl hydrazine and regenerate the active catalyst. The reaction sequence is likely to be similar for intramolecular reactions. Alternatively, and particularly for nickel catalysts, the active transition metal species in the oxidative addition step may involve the metal in the +1 oxidation state. 
In preferred embodiments of the invention, there is no need to use large excesses of either reactantxe2x80x94hydrazine and the like or aromatic compound. The reaction proceeds quickly and in high yield to the reaction product using substantially stoichiometric amounts of reagents. Thus, the hydrazine may be present in as little as a two-fold excess and preferably in no greater than a 20% excess relative to the aromatic compound. Alternatively, the aromatic compound may be present in as little as a two-fold excess and preferably in no greater than a 20% excess relative to the hydrazine.
The reaction can proceed at mild temperatures and pressures to give high yields of the product aryl hydrazine or the like. Thus, yields of greater than 45%, preferably greater than 75% and even more preferably greater than 80% may be obtained by reaction at mild temperatures according to the invention. The reaction may be carried out at temperature less than 120xc2x0 C., and preferably in the range of 50-120xc2x0 C. In one preferred embodiment, the reaction is carried out at a temperature in the range of 80-100xc2x0 C.
The reaction can be run in a wide range of solvent systems, including polar aprotic solvents. Alternatively, in certain embodiments, the subject reactions may be carried in the absence of added solvent.
The ability to provide a synthesis scheme for hydrazines and the like which can be carried out under mild conditions and/or with non-polar solvents has broad application, especially in the agricultural and pharmaceutical industries, as well as in the polymer industry. In this regard, the subject reaction is more amenable to use of reactants or products which include sensitive functionalities, e.g., which would otherwise be labile under harsh reaction conditions.
The subject hydrazine arylation reactions can be used as part of a combinatorial synthesis scheme to yield libraries of aryl hydrazines and the like. Accordingly, another aspect of the present invention relates to use of the subject method to generate variegated libraries of aryl hydrazines and the like, and to the libraries themselves. The libraries can be soluble or linked to insoluble supports, e.g., either through substituents of the aryl group or the hydrazine etc.
Definitions
For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here.
The term xe2x80x9csubstrate aryl groupxe2x80x9d refers to an aryl group containing an electrophilic atom which is susceptible to the subject cross-coupling reaction, e.g., the electrophilic atom bears a leaving group. In reaction scheme 1, the substrate aryl is represented by ArX, and X is the leaving group. The aryl group, Ar, is said to be substituted if, in addition to X, it is substituted at yet other positions. The substrate aryl group can be a single ring molecule, or can be a component of a larger molecule.
The terms xe2x80x9chydrazine and/or the likexe2x80x9d refer to a hydrazine, hydrazone, hydroxylamine, oxime etc. which can attack the electrophilic atom of the substrate aryl group and displace the leaving group in the subject cross-coupling reaction. In Schemes 1 and 2, the nucleophilic hydrazine and/or the like are represented by HN(R)xe2x80x94Y, and HYxe2x80x94NR2, respectively. The hydrazine and/or the like can be a component of a molecule separate from the substrate aryl group, or a substituent of the same molecule (e.g., for intramolecular cross couplings).
The term xe2x80x9cnucleophilexe2x80x9d is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.
The term xe2x80x9celectrophilexe2x80x9d is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above. Electrophilic moieties useful in the method of the present invention include halides and sulfonates.
The terms xe2x80x9celectrophilic atomxe2x80x9d, xe2x80x9celectrophilic centerxe2x80x9d and xe2x80x9creactive centerxe2x80x9d as used herein refer to the atom of the substrate aryl moiety which is attacked by, and forms a new bond to the nucleophilic heteroatom of the hydrazine and the like. In most (but not all) cases, this will also be the aryl ring atom from which the leaving group departs.
The term xe2x80x9celectron-withdrawing groupxe2x80x9d is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron-withdrawing capability is given by the Hammett sigma (s) constant. This well known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259. The Hammett constant values are generally negative for electron donating groups (s[P]=xe2x88x920.66 for NH2) and positive for electron withdrawing groups (s[P]=0.78 for a nitro group), s[P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, xe2x80x94CN, chloride, and the like. Exemplary electron-donating groups include amino, methoxy, and the like.
The term xe2x80x9creaction productxe2x80x9d means a compound which results from the reaction of the hydrazine or the like and the substrate aryl group. In general, the term xe2x80x9creaction productxe2x80x9d will be used herein to refer to a stable, isolable aryl ether adduct, and not to unstable intermediates or transition states.
The term xe2x80x9ccatalytic amountxe2x80x9d is recognized in the art and means a substoichiometric amount of reagent relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent reagent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent reagent to reactant.
The term xe2x80x9calkylxe2x80x9d refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
Moreover, the term xe2x80x9calkylxe2x80x9d (or xe2x80x9clower alkylxe2x80x9d) as used throughout the specification and claims is intended to include both xe2x80x9cunsubstituted alkylsxe2x80x9d and xe2x80x9csubstituted alkylsxe2x80x9d, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, a formyl, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thiolformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, iamido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), xe2x80x94CF3, xe2x80x94CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, xe2x80x94CF3, xe2x80x94CN, and the like.
The term xe2x80x9caralkylxe2x80x9d, as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
Unless the number of carbons is otherwise specified, xe2x80x9clower alkylxe2x80x9d as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, xe2x80x9clower alkenylxe2x80x9d and xe2x80x9clower alkynylxe2x80x9d have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
The term xe2x80x9carylxe2x80x9d as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as xe2x80x9caryl heterocyclesxe2x80x9d or xe2x80x9cheteroaromaticsxe2x80x9d. The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, xe2x80x94CF3, xe2x80x94CN, or the like. The term xe2x80x9carylxe2x80x9d also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are xe2x80x9cfused ringsxe2x80x9d) wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, xe2x80x94CF3, xe2x80x94CN, or the like.
The terms xe2x80x9cpolycyclylxe2x80x9d or xe2x80x9cpolycyclic groupxe2x80x9d refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are xe2x80x9cfused ringsxe2x80x9d. Rings that are joined through non-adjacent atoms are termed xe2x80x9cbridgedxe2x80x9d rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, xe2x80x94CF3, xe2x80x94CN, or the like.
The term xe2x80x9ccarbocyclexe2x80x9d, as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
The term xe2x80x9cheteroatomxe2x80x9d as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorous.
As used herein, the term xe2x80x9cnitroxe2x80x9d means xe2x80x94NO2; the term xe2x80x9chalogenxe2x80x9d designates xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I; the term xe2x80x9csulfhydrylxe2x80x9d means xe2x80x94SH; the term xe2x80x9chydroxylxe2x80x9d means xe2x80x94OH; and the term xe2x80x9csulfonylxe2x80x9d means xe2x80x94SO2xe2x80x94.
The terms xe2x80x9caminexe2x80x9d and xe2x80x9caminoxe2x80x9d are art recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula: 
wherein R9, R10 and Rxe2x80x210 each independently represent a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R8, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In preferred embodiments, only one of R9 or R10 can be a carbonyl, e.g., R9, R10 and the nitrogen together do not form an imide. In even more preferred embodiments, R9 and R10 (and optionally Rxe2x80x210) each independently represent a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mxe2x80x94R8. Thus, the term xe2x80x9calkylaminexe2x80x9d as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R9 and R10 is an alkyl group.
The term xe2x80x9cacylaminoxe2x80x9d is art-recognized and refers to a moiety that can be represented by the general formula: 
wherein R9 is as defined above, and Rxe2x80x211 represents a hydrogen, an alkyl, an alkenyl or xe2x80x94(CH2)mxe2x80x94R8, where m and R8 are as defined above.
The term xe2x80x9camidoxe2x80x9d is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: 
wherein R9, R10 are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.
The term xe2x80x9calkylthioxe2x80x9d refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the xe2x80x9calkylthioxe2x80x9d moiety is represented by one of xe2x80x94S-alkyl, xe2x80x94S-alkenyl, xe2x80x94S-alkynyl, and xe2x80x94Sxe2x80x94(CH2)mxe2x80x94R8, wherein m and R8 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.
The term xe2x80x9ccarbonylxe2x80x9d is art recognized and includes such moieties as can be represented by the general formula: 
wherein X is a bond or represents an oxygen or a sulfur, and R11 represents a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R8 or a pharmaceutically acceptable salt, Rxe2x80x211 represents a hydrogen, an alkyl, an alkenyl or xe2x80x94(CH2)mxe2x80x94R8, where m and R8 are as defined above. Where X is an oxygen and R11 or Rxe2x80x211 is not hydrogen, the formula represents an xe2x80x9cesterxe2x80x9d. Where X is an oxygen, and R11 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R11 is a hydrogen, the formula represents a xe2x80x9ccarboxylic acidxe2x80x9d. Where X is an oxygen, and Rxe2x80x211 is hydrogen, the formula represents a xe2x80x9cformatexe2x80x9d. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a xe2x80x9cthiolcarbonylxe2x80x9d group. Where X is a sulfur and R11 or Rxe2x80x211 is not hydrogen, the formula represents a xe2x80x9cthiolester.xe2x80x9d Where X is a sulfur and R11 is hydrogen, the formula represents a xe2x80x9cthiolcarboxylic acid.xe2x80x9d Where X is a sulfur and R11 is hydrogen, the formula represents a xe2x80x9cthiolformate.xe2x80x9d On the other hand, where X is a bond, and R11 is not hydrogen, the above formula represents a xe2x80x9cketonexe2x80x9d group. Where X is a bond, and R11 is hydrogen, the above formula represents an xe2x80x9caldehydexe2x80x9d group.
The terms xe2x80x9calkoxylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An xe2x80x9cetherxe2x80x9d is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-alkynyl, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R8, where m and R8 are described above.
The term xe2x80x9csulfonatexe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
The term xe2x80x9csulfatexe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R41 is as defined above.
The term xe2x80x9csulfonamidoxe2x80x9d is art recognized and includes a moiety that can be represented by the general formula: 
in which R9 and Rxe2x80x211 are as defined above.
The term xe2x80x9csulfamoylxe2x80x9d is art-recognized and includes a moiety that can be represented by the general formula: 
in which R9 and R10 are as defined above.
The terms xe2x80x9csulfoxidoxe2x80x9d or xe2x80x9csulfinylxe2x80x9d, as used herein, refers to a moiety that can be represented by the general formula: 
in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
A xe2x80x9cphosphorylxe2x80x9d can in general be represented by the formula: 
wherein Q1 represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: 
wherein Q1 represented S or O, and each R46 independently represents hydrogen, a lower alkyl or an aryl, Q2 represents O, S or N. When Q1 is an S, the phosphoryl moiety is a xe2x80x9cphosphorothioatexe2x80x9d.
A xe2x80x9cphosphoramiditexe2x80x9d can be represented in the general formula: 
wherein R9 and R10 are as defined above, and Q2 represents O, S or N.
A xe2x80x9cphosphoramiditexe2x80x9d can be represented in the general formula: 
wherein R9 and R10 are as defined above, Q2 represents O, S or N, and R48 represents a lower alkyl or an aryl, Q2 represents O, S or N.
A xe2x80x9cselenoalkylxe2x80x9d refers to an alkyl group having a substituted seleno group attached thereto. Exemplary xe2x80x9cselenoethersxe2x80x9d which may be substituted on the alkyl are selected from one of xe2x80x94Se-alkyl, xe2x80x94Se-alkenyl, xe2x80x94Se-alkynyl, and xe2x80x94Sexe2x80x94(CH2)mxe2x80x94R8, m and R8 being defined above.
Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
The phrase xe2x80x9cprotecting groupxe2x80x9d as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
It will be understood that xe2x80x9csubstitutionxe2x80x9d or xe2x80x9csubstituted withxe2x80x9d includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
A xe2x80x9cpolar solventxe2x80x9d means a solvent which has a dipole moment (xcex5) of 2.9 or greater, such as DMF, THF, ethylene gylcol dimethyl ether, DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol, t-butanol or 2-methoxyethyl ether. Preferred solvents are DMF, diglyme, and acetonitrile.
A xe2x80x9cpolar, aprotic solventxe2x80x9d means a polar solvent as defined above which has no available hydrogens to exchange with the compounds of this invention during reaction, for example DMF, acetonitrile, diglyme, DMSO, or THF.
An xe2x80x9caprotic solventxe2x80x9d means a non-nucleophilic solvent having a boiling point range above ambient temperature, preferably from about 25xc2x0 C. to about 190xc2x0 C., more preferably from about 80xc2x0 C. to about 160xc2x0 C., most preferably from about 80xc2x0 C. to 150xc2x0 C., at atmospheric pressure. Examples of such solvents are acetonitrile, toluene, DMF, diglyme, THF or DMSO.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term xe2x80x9chydrocarbonxe2x80x9d is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
II. Exemplary Catalyzed Reactions
As described above, one invention of the Applicants"" features a transition metal-catalyzed cross-coupling reaction which comprises combining a hydrazine with an aryl group (a xe2x80x9csubstrate arylxe2x80x9d) bearing an activated group X. The reaction includes at least a catalytic amount of a transition metal catalyst and the combination is maintained under conditions appropriate for the metal catalyst to catalyze the nucleophilic addition of the reactive hydrazine to the electrophilic atom of the substrate aryl.
In an illustrative embodiment, the subject method can be used for the intermolecular reaction between an activated aryl substrate and a hydrazine to give an aryl hydrazine: 
In a second illustrative embodiment, the subject method can be used to bring about an intramolecular arylation of a hydrazine; said arylation yields a diazaheterocycle. In some cases, including the case illustrated below, the initially-formed diazaheterocycle can be oxidized to yield a new diazaaromatic compound: 
Another aspect of the Applicants"" invention features a transition metal-catalyzed cross-coupling reaction which comprises combining a hydroxylamine with an aryl group (a xe2x80x9csubstrate arylxe2x80x9d) being an activated group X. The reaction includes at least a catalytic amount of a transition metal catalyst and the combination is maintained under conditions appropriate for the metal catalyst to catalyze the nucleophilic addition of a reactive nitrogen or oxygen of a hydroxylamine, depending upon substrates and conditions selected, or a reactive oxygen of an oxime to the electrophilic atom of the substrate aryl.
In an embodiment illustrative of this aspect of the invention, the subject method can be exploited for the preparation of an O-alkenyl oxime from a vinyl halide and an oxime: 
In an second embodiment illustrative of this aspect of the invention, the subject method can be exploited in the arylation of an O-alkyl hydroxylamine to give an N-aryl-O-alkyl hydroxylamine: 
Intramolecular variants are available of the aspects of the invention that center on hydroxyl amines. An illustrative embodiment is shown below: 
A second illustrative embodiment of an intramolecular arylation of a hydroxyl amine is shown below. Also illustrated below is the potential for the preparation of 1,n-amino alcohols via a subsequent reduction of the nitrogen-oxygen single bond in products of the subject arylation. 
The subject method can be applied to the synthesis of N-arylhydrazones. A preferred embodiment, illustrated below, involves the transition metal catalyzed arylation of benzophenone hydrazone: 
In still another illustrative embodiment, the subject reaction between a hydrazone and an activated aryl substrate, followed by reduction of the resulting N-aryl hydrazone, can be utilized for the synthesis of anilines: 
In a highly preferred illustrative embodiment, the subject arylation of benzophenone hydrazone is the initial step in a conceptually novel entry into the Fischer indole synthesis. The entire sequence of events in this novel strategy for indole synthesis is illustrated below. The second step in this strategy involves two discrete events: 1) an acid-catalyzed exchange of a new aldehyde or ketone for benzophenone to form a new hydrazonexe2x80x94labeled xe2x80x9cnot isolatedxe2x80x9dxe2x80x94and benzophenone (not shown); and 2) the acid-catalyzed formation of an indole from the second hydrazone via what is known in the art as the Fischer Indole synthesis: 
In another highly preferred illustrative embodiment, the subject arylation of benzophenone hydrazone is followed by a second subject arylation to give an N,N-diaryl benzophenone hydrazone. The subsequent step of this embodiment is the acid-catalyzed xe2x80x9cexchange inxe2x80x9d of a new carbonyl component to produce benzophenone and a new hydrazone (refer to the teachings of the preceding illustrative example); the new hydrazone then undergoes an acid-catalyzed Fischer indole synthesis reaction to give the product indole. The Fischer indole synthesis step in this embodiment is highly selective; the more electron-rich aryl moiety of the intermediate N,N-diaryl hydrazone is selectively incorporated into the indole nucleus of the product, and the less electron-rich aryl moiety appears as a substituent at the 1-position of the indole product. 
In an additional highly preferred embodiment, the arylation-Fischer Indole synthesis strategy is carried out on a solid support: 
In a further highly preferred embodiment, a combinatorial approach to the arylation-Fischer Indole synthesis strategy on a solid support is pursued to yield a library of indoles: 
In another highly preferred embodiment, the subject arylation of an oxime can be followed by a step analogous to the Fischer indole synthesis to provide a benzofuran: 
In a highly preferred embodiment, the subject vinylation of a hydrazone can be followed by a step analogous to the Fischer indole synthesis to provide a pyrrole: 
The substrate aryl compounds include compounds derived from simple aromatic rings (single or polycylic) such as benzene, naphthalene, anthracene and phenanthrene; or heteroaromatic rings (single or polycyclic), such as pyrrole, thiophene, thianthrene, furan, pyran, isobenzofluran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, thiazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, perimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine and the like. In preferred embodiment, the reactive group, X, is substituted on a five, six or seven membered ring (though it can be part of a larger polycyle).
In preferred embodiments, the aryl substrate may be selected from the group consisting of phenyl and phenyl derivatives, heteroaromatic compounds, polycyclic aromatic and heteroaromatic compounds, and functionalized derivatives thereof. Suitable aromatic compounds derived from simple aromatic rings and heteroaromatic rings, include but are not limited to, pyridine, imidizole, quinoline, furan, pyrrole, thiophene, and the like. Suitable aromatic compounds derived from fused ring systems, include but are not limited to naphthalene, anthracene, tetralin, indole and the like.
Suitable aromatic compounds may have the formula ZpArX, where X is an activated substituent. An activated substituent, X, is characterized as being a good leaving group. In general, the leaving group is a group such as a halide or sulfonate. For the purposes of the present invention, an activated substituent is that moiety whose conjugate acid, HX, has a pKa of less than 5.0. Suitable activated substituents include, by way of example only, halides such as chloride, bromide and iodide, and sulfonate esters such as triflate, mesylate, nonaflate and tosylate. In certain embodiments, the leaving group is a halide selected from iodine and bromine. Chlorine and fluorine can also be used as leaving groups, though other electronegative substitution on the aryl group may be required to activate those halogens as leaving groups in the subject metal cross-coupling reactions.
Z represents one or more optional substituents on the aromatic ring, though each occurence of Z (p greater than 1) is independently selected. By way of example only, each incidence of substitution independently can be, as valence and stability permit, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (e.g., an ester, a carboxylate, or a formate), a thiocarbonyl (e.g., a thiolester, a thiolcarboxylate, or a thiolformate), a ketyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, xe2x80x94(CH2)mxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94OH, xe2x80x94(CH2)mxe2x80x94O-lower alkyl, xe2x80x94(CH2)mxe2x80x94O-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94R8, xe2x80x94(CH2)mxe2x80x94SH, xe2x80x94(CH2)mxe2x80x94S-lower alkyl, xe2x80x94(CH2)mxe2x80x94S-lower alkenyl, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94R8, or protecting groups of the above or a solid or polymeric support; R8 represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and n and m are independently for each occurrence zero or an integer in the range of 1 to 6. P is preferably in the range of 0 to 5. For fused rings, where the number of substitution sites on the aryl group increases, p may be adjusted appropriately.
In certain embodiments, suitable substituents Z include alkyl, aryl, acyl, heteroaryl, amino, carboxylic ester, carboxylic acid, hydrogen group, ether, thioether, amide, carboxamide, nitro, phosphonic acid, hydroxyl, sulfonic acid, halide, pseudohalide groups, and substituted derivatives thereof, and p is in the range of 0 to 5. In particular, the reaction has been found compatible with acetals, amides and silyl ethers as functional groups. For fused rings, where the number of substitution sites on the aromatic ring increases, p may be adjusted appropriately. In addition, the above mentioned moieties may be covalently linked to an alcohol moiety in intramolecular reactions.
In preferred embodiments, the resonance structure of the aryl group Ar, or at least one substituent Z, is electron-withdrawing from the substituted position of X.
A wide variety of substrate aryl groups are useful in the methods of the present invention. The choice of substrate will depend on factors such as the hydrazine or the like to be employed and the desired product, and an appropriate aryl substrate will be apparent to the skilled artisan. It will be understood that the aryl substrate preferably will not contain any interfering functionalities. It will further be understood that not all activated aryl substrates will react with every alcohol.
The reactive hydrazine group or the like can be a molecule separate from the substrate aryl group, or a substituent of the same molecule (e.g., for intramolecular condensation).
The hydrazine or the like is selected to provide the desired reaction product. In general, the hydrazine or the like may be selected from the set comprising hydrazines, hydrazones, hydroxylamines and the like. The hydrazine or the like may be functionalized. The hydrazine or the like may be selected from a wide variety of structural types, including but not limited to, acyclic, cyclic or heterocyclic compounds, fused ring compounds or phenol derivatives. The aromatic compound and the hydrazine or the like may be included as moieties of a single molecule, whereby the arylation reaction proceeds as an intramolecular reaction.
In certain embodiments, the reactive hydrazine group or the like which is used in the subject coupling reaction can be represented by general formula RHNxe2x80x94Y or HYxe2x80x94NR2. R represents, as valence and stability permit, a substituted or unsubstituted alkyl or alkenyl group, or xe2x80x94(CH2)mxe2x80x94R8, wherein R8 represents a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle, and m is zero or an integer in the range of 1 to 8. In other embodiments, R is linker to a solid support.
In certain embodiments, the hydrazine or the like is generated in situ by conversion of a precursor under the reaction conditions, e.g. by deprotonation of a hydrohalide salt of the hydrazine or the like.
Alternatively, the corresponding hydrazide or the like salt, e.g., NaN(R)xe2x80x94Y, LiN(R)xe2x80x94Y, KN(R)xe2x80x94Y, NaYxe2x80x94NR2, LiYxe2x80x94NR2, KYxe2x80x94NR2, etc., may be prepared and used in place of the hydrazine or the like. When the corresponding hydrazide or the like is used in the reaction, an additional base may not be required.
The active form of the transition metal catalyst is not well characterized. Therefore, it is contemplated that the xe2x80x9ctransition metal catalystxe2x80x9d of the present invention, as that term is used herein, shall include any catalytic transition metal and/or catalyst precursor as it is introduced into the reaction vessel and which is, if necessary, converted in situ into the active form, as well as the active form of the catalyst which participates in the reaction.
In preferred embodiments, the transition metal catalyst complex is provided in the reaction mixture is a catalytic amount. In certain embodiments, that amount is in the range of 0.0001 to 20 mol %, and preferably 0.05 to 5 mol %, and most preferably 1-3 mol %, with respect to the limiting reagent, which may be either the aromatic compound or the hydrazine or the like (or corresponding hydrazide etc.) or both, depending upon which reagent is in stoichiometric excess. In the instance where the molecular formula of the catalyst complex includes more than one metal, the amount of the catalyst complex used in the reaction may be adjusted accordingly. By way of example, Pd2(dba)3 has two metal centers; and thus the molar amount of Pd2(dba)3 used in the reaction may be halved without sacrifice to catalytic activity.
Additionally, heterogeneous catalysts containing forms of these elements are also suitable catalysts for any of the transition metal catalyzed reactions of the present invention. Catalysts containing palladium and nickel are preferred. It is expected that these catalysts will perform similarly because they are known to undergo similar reactions, namely oxidative-addition reactions and reductive-elimination reactions, which are thought to be involved in the formation of the aryl hydrazines etc. of the present invention. However, the different ligands are thought to modify the catalyst performance by, for example, modifying reactivity and preventing undesirable side reactions.
As suitable, the catalysts employed in the subject method involve the use of metals which can mediate cross-coupling of the aryl groups ArX and the hydrazine or the like as defined above. In general, any transition metal (e.g., having d electrons) may be used to form the catalyst, e.g., a metal selected from one of Groups 3-12 of the periodic table or from the lanthanide series. However, in preferred embodiments, the metal will be selected from the group of late transition metals, e.g. preferably from Groups 5-12 and even more preferably Groups 7-11. For example, suitable metals include platinum, palladium, iron, nickel, ruthenium and rhodium. The particular form of the metal to be used in the reaction is selected to provide, under the reaction conditions, metal centers which are coordinately unsaturated and not in their highest oxidation state. The metal core of the catalyst should be a zero valent transition metal, such as Pd or Ni with the ability to undergo oxidative addition to Ar-X bond. The zero-valent state, M0, may be generated in situ from M+2.
To further illustrate, suitable transition metal catalysts include soluble or insoluble complexes of platinum, palladium and nickel. Nickel and palladium are particularly preferred and palladium is most preferred. A zero-valent metal center is presumed to participate in the catalytic carbon-heteroatom bond forming sequence. Thus, the metal center is desirably in the zero-valent state or is capable of being reduced to metal(0). Suitable soluble palladium complexes include, but are not limited to, tris(dibenzylideneacetone) dipalladium [Pd2(dba)3], bis(dibenzylideneacetone) palladium [Pd(dba)2] and palladium acetate. Suitable catalysts for a heterogeneous arylation reaction include, but are not limited to, palladium on carbon (Pd/C). Alternatively, particularly for nickel catalysts, the active species for the oxidative-addition step may be in the metal (+1) oxidative-addition state.
Catalysts containing palladium and nickel are preferred. It is expected that these catalysts will perform comparably because they are known to undergo similar reactions, namely cross-coupling reactions, which may be involved in the formation of the aryl hydrazines etc. of the present invention.
The coupling can be catalyzed by a palladium catalyst which may take the form of, to illustrate, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6H5)3]4, and polymer supported Pd(0). In other embodiments, the reaction can be catalyzed by a nickel catalyst, such as Ni(acac)2, NiCl2[P(C6H5)]2, Ni(1,5-cyclooctadiene)2, Ni(1,10-phenanthroline)2, Ni(dppf)2, NiC2(dppf), NiCl2(1,10-phenanthroline), Raney nickel and the like, wherein xe2x80x9cacacxe2x80x9d represents acetylacetonate.
The catalyst will preferably be provided in the reaction mixture as metal-ligand complex comprising a bound supporting ligand, that is, a metal-supporting ligand complex. The ligand effects can be key to favoring, inter alia, the reductive elimination pathway or the like which produces the hydrazine or the like, over such side reactions as xcex2-hydride elimination. In particular, the use of bulky and less electron-donating ligands (but probably still chelating ligands) should favor the reductive elimination process. In preferred embodiments, the subject reaction employs bulky bidentate ligands such as bisphosphines.
The ligand, as described in greater detail below, may include chelating ligands, such as by way of example only, alkyl and aryl derivatives of phosphines and bisphosphines, amines, diamines, imines, arsines, and hybrids thereof, including hybrids of phosphines with amines. Weakly or non-nucleophilic stabilizing ions are preferred to avoid complicating side reaction of the counter ion attacking or adding to the electrophilic center of the substrate aryl. This catalyst complex may include additional ligands as is necessary to obtain a stable complex. Moreover, the ligand can be added to the reaction mixture in the form of a metal complex, or added as a separate reagent relative to the addition of the metal. By way of example, PdC2(BINAP) may be prepared in a separate step and used as the catalyst complex set forth in Schemes 1-7.
The ligand, if chiral can be provided as a racemic mixture or a purified stereoisomer.
The supporting ligand may be added to the reaction solution as a separate compound or it may be complexed to the metal center to form a metal-supporting ligand complex prior to its introduction into the reaction solution. Supporting ligands are compounds added to the reaction solution which are capable of binding to the catalyst metal center, although an actual metal-supporting ligand complex has not been identified in each and every synthesis. In some preferred embodiments, the supporting ligand is a chelating ligand. Although not bound by any theory of operation, it is hypothesized that the supporting ligands prevent unwanted side reactions as well as enhancing the rate and efficiency of the desired process. Additionally, they typically prevent precipitation of the catalytic transition metal. Although the present invention does not require the formation of a metal-supporting ligand complex, such complexes have been shown to be consistent with the postulate that they are intermediates in these reactions and it has been observed the selection of the supporting ligand has an affect on the course of the reaction.
The supporting ligand is present in the range of 0.0001 to 40 mol% relative to the limiting reagent, i.e., hydrazine etc. or aromatic compound. The ratio of the supporting ligand to catalyst complex is typically in the range of about 1 to 20, and preferably in the range of about 1 to 4 and most preferably 2. These ratios are based upon a single metal complex and a single binding site ligand. In instances where the ligand contains additional binding sites (i.e., a chelating ligand) or the catalyst contains more than one metal, the ratio is adjusted accordingly. By way of example, the supporting ligand BINAP contains two coordinating phosphorus atoms and thus the ratio of BINAP to catalyst is adjusted downward to about 1 to 10, preferably about 1 to 2 and most preferably 1. Conversely, Pd2(dba)3 contains two palladium metal centers and the ratio of a non-chelating ligand to Pd2(dba)3 is adjusted upward to 1 to 40, preferably 1 to 8 and most preferably 4.
In certain embodiments of the subject method, the transition metal catalyst includes one or more phosphine ligands, e.g., as a Lewis basic ligand that controls the stability and electron transfer properties of the transition metal catalyst, and/or stabilizes the metal intermediates. Phosphine ligands are commercially available or can be prepared by methods similar to processes known per se. The phosphines can be monodentate phosphine ligands, such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, tricyclohexylphosphine, trimethyl phosphite, triethyl phosphite, tripropyl phosphite, triisopropyl phosphite, tributyl phosphite and tricyclohexyl phosphite, in particular triphenylphosphine, tri(o-tolyl)phosphine, triisopropylphosphine or tricyclohexylphosphine; or a bidentate phosphine ligand such as 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (BINAP), 1,2-bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphino)ethane, 1,2-bis(dipropylphosphino)ethane, 1,2-bis(diisopropylphosphino)ethane, 1,2-bis(dibutyl-phosphino)ethane, 1,2-bis(dicyclohexylphosphino)ethane, 1,3-bis(dicyclohexylphosphino)propane, 1,3-bis(diiso-propylphosphino)propane, 1,4-bis(diisopropylphosphino)-butane and 2,4-bis(dicyclohexylphosphino)pentane.
In preferred embodiments, the phosphine ligand is one (or a mix of) of P(o-tolyl)3. Bis(phosphine) ligands are particularly preferred chelating supporting ligands. Suitable bis(phosphine) compounds include but are in no way limited to (xc2x1)-2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl (and separate enantiomers), (xc2x1)-2,2xe2x80x2-bis(di-p-tolylphosphino)-1,1xe2x80x2-binaphthyl (and separate enantiomers), 1-1xe2x80x2-bis(diphenylphosphino)ferrocene (dppf), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)benzene, 2,2xe2x80x2-bis(diphenylphosphino)diphenyl ether, and 1,2-bis(diphenylphosphino)ethane (dppe). Hybrid chelating ligands such as (xc2x1)-N,N-dimethyl-1-[2-(diphenylphosphino) ferrocenyl]ethylamine (and separate enantiomers), and (xc2x1)-(R)-1-[(S)-2-(diphenylphosphino)-ferrocenyl]ethyl methyl ether (and separate enantiomers) are also within the scope of the invention.
In some instances, it may be necessary to include additional reagents in the reaction to promote reactivity of either the transition metal catalyst or activated aryl nucleus. In particular, it may be advantageous to include a suitable base. In general, a variety of bases may be used in practice of the present invention. It has not been determined if deprotonation occurs prior to or after heteroatom coordination to the transition metal of the active catalyst. The base may optionally be sterically hindered to discourage metal coordination of the base in those circumstances where such coordination is possible, i.e., alkali metal alkoxides. Exemplary bases include such as, for example: an alkoxides such as sodium tert-butoxide, an alkali metal amide such as sodium amide, lithium diisopropylamide or an alkali metal bis(trialkylsilyl)amides, e.g., such as lithium bis(trimethylsilyl)amide or sodium bis(trimethylsilyl) amide, a tertiary amine (e.g. triethylamine, trimethylamine, 4-(dimethylamino)pyridine (DMAP), 1,5-diazabicycl[4.3.0]non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), alkali, alkaline earth carbonate, bicarbonate or hydroxide (e.g. sodium, magnesium, calcium, barium, potassium carbonate, hydroxide and bicarbonate). By way of example only, suitable bases include NaH, LiH, KH, K2CO3, Na2CO3, Tl2CO3, Cs2CO3, K(OtBu), Li(OtBu), Na(OtBu) K(OPh), Na(OPh), triethylamine or mixtures thereof NaH, Na(OtBu) and K2CO3 have been found useful in a wide variety of aryl ether bond forming reactions. Preferred bases include Cs2CO3, DBU, NaH, KOt-Bu, LiN(i-Pr)2 (LDA), KN(SiMe3)2, NaN(SiMe3)2, and LiN(SiMe3)2.
Base is used in approximately stoichiometric proportions in reactions using hydrazines etc. The present invention has demonstrated that there is no need for large excesses of base in order to obtain good yields of aryl hydrazines etc. under mild reaction conditions. No more than four equivalents and preferably no more than two equivalents are needed. Further, in reactions using the corresponding hydrazide etc. as the reagent, there may be no need for additional base.
In this way a wide range of aryl hydrazines, aryl hydrazones, and N- and O-aryl hydroxylamines may be prepared from available hydrazines, hydrazones and hydroxylamines and the corresponding hydrohalide salts. The reaction can be accomplished using a wide range of hydrazines and the like, which are either commercially available or obtainable from conventional syntheses using a variety of methods known in the art.
As is clear from the above discussion, the products which may be produced by the arylation reaction of this invention can undergo further reaction(s) to afford desired derivatives thereof. Such permissible derivatization reactions can be carried out in accordance with conventional procedures known in the art. For example, potential derivatization reactions include esterification, oxidation of alcohols to aldehydes and acids, N-alkylation of amides, nitrile reduction, acylation of alcohols by esters, acylation of amines and the like.
III. Reaction Conditions
The arylation reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention.
In general, it will be desirable that reactions are run using mild conditions which will not adversely affect the reactants, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants and catalyst. The reactions will usually be run at temperatures in the range of 25xc2x0 C. to 300xc2x0 C., more preferably in the range 25xc2x0 C. to 150xc2x0 C.
In general, the subject reactions are carried out in a liquid reaction medium. The reactions may be run without addition of solvent. Alternatively, the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, xylene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents.
The invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be preferred to perform the catalyzed reactions in the solid phase with one of the reactants anchored to a solid support.
In certain embodiments it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon.
The reaction processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle operation as desired. The processes of this invention are preferably conducted in batch fashion. Likewise, the manner or order of addition of the reaction ingredients, catalyst and solvent are also not generally critical and may be accomplished in any conventional fashion. In a preferred order of events that leads to an enhancement of the reaction rate, the base, e.g. t-BuONa, is the last ingredient to be added to the reaction mixture.
The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures. Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the metal catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
The processes may be conducted in either glass lined, stainless steel or similar type reaction equipment. The reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible xe2x80x9crunawayxe2x80x9d reaction temperatures.
Furthermore, one or more of the reactants can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, derivativation with one or more of substituents of the aryl group.
IV. Combinatorial Libraries
The subject arylation reaction readily lends itself to the creation of combinatorial libraries of aryl hydrazines, aryl hydrazones, N- and O-aryl hydroxylamines, and indoles for the screening of pharmaceutical, agrochemical or other biological or medically-related activity or material-related qualities. A combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently linked to a solid support. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening processes which need to be carried out. Screening for the appropriate biological, pharmaceutical, agrochemical or physical property is done by conventional methods.
Diversity in the library can be created at a variety of different levels. For instance, the substrate aryl groups used in the combinatorial reactions can be diverse in terms of the core aryl moiety, e.g., a variegation in terms of the ring structure, and/or can be varied with respect to the other substituents.
A variety of techniques are available in the art for generating combinatorial libraries of small organic molecules such as the subject aryl hydrazines etc. and indoles. See, for example, Blondelle et al. (1995) Trends Anal. Chem. 14:83; the Affymax U.S. Pat. Nos. 5,359,115 and 5,362,899: the Ellman U.S. Pat. No. 5,288,514: the Still et al. PCT publication WO 94/08051; Chen et al. (1994) JACS 116:2661: Kerr et al. (1993) JACS 115:252; PCT publications WO92/10092, WO93/09668 and WO91/07087; and the Lemer et al. PCT publication WO93/20242). Accordingly, a variety of libraries on the order of about 16 to 1,000,000 or more diversomers of the subject aryl hydrazines etc. or indoles can be synthesized and screened for particular activity or property.
In an exemplary embodiment, a library of substituted diversomers can be synthesized using the subject cross-coupling reaction adapted to the techniques described in the Still et al. PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyzable or photolyzable group e.g., located at one of the positions of the aryl group or a substituent of the hydrazine and the like. According to the Still et al. technique, the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead. In one embodiment, which is particularly suitable for discovering enzyme inhibitors, the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay.
Exemplification
The invention may be understood with reference to the following examples, which are presented for illustrative purposes only and which are non-limiting. Hydrazines, hydrazones, ketones and aromatic halides utilized as substrates in these examples were either commercially available or were prepared in three or less steps from commercially available reagents. Palladium catalysts were all commercially available.